title: Minireview: Novel aspects of M3 muscarinic receptor signaling in pancreatic β-cells.
abstract: The release of insulin from pancreatic β-cells is regulated by a considerable number of G protein-coupled receptors. During the past several years, we have focused on the physiological importance of β-cell M3 muscarinic acetylcholine receptors (M3Rs). At the molecular level, the M3R selectively activates G proteins of the G(q) family. Phenotypic analysis of several M3R mutant mouse models, including a mouse strain that lacks M3Rs only in pancreatic β-cells, indicated that β-cell M3Rs play a key role in maintaining blood glucose levels within a normal range. Additional studies with transgenic M3R mouse models strongly suggest that strategies aimed to enhance signaling through β-cell M3Rs may prove useful in the treatment of type 2 diabetes. More recently, we analyzed transgenic mice that expressed an M3R-based designer receptor in a β-cell-specific fashion, which enabled us to chronically activate a β-cell G(q)-coupled receptor by a drug that is otherwise pharmacologically inert. Drug-dependent activation of this designer receptor stimulated the sequential activation of G(q), phospholipase C, ERK1/2, and insulin receptor substrate 2 signaling, thus triggering a series of events that greatly improved β-cell function. Most importantly, chronic stimulation of this pathway protected mice against experimentally induced diabetes and glucose intolerance, induced either by streptozotocin or by the consumption of an energy-rich, high-fat diet. Because β-cells are endowed with numerous receptors that mediate their cellular effects via activation of G(q)-type G proteins, these findings provide a rational basis for the development of novel antidiabetic drugs targeting this class of receptors.
authors.affiliation: Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland 20892, USA.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Nakajima
authors.forename: Shalini
authors.initials: S
authors.lastname: Jain
authors.forename: Inigo
authors.initials: I
authors.lastname: Ruiz de Azua
authors.forename: Sara M
authors.initials: SM
authors.lastname: McMillin
authors.forename: Mario
authors.initials: M
authors.lastname: Rossi
authors.forename: Jürgen
authors.initials: J
authors.lastname: Wess
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000517:prevention & control*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D018149:Glucose Intolerance / Q000188:drug therapy / Q000517:prevention & control*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000187:drug effects / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D043587:Receptor, Muscarinic M3 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000187:drug effects / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D055504:Insulin Receptor Substrate Proteins; D043587:Receptor, Muscarinic M3; D048049:Extracellular Signal-Regulated MAP Kinases; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins